CVANS: The Structure Function

Autonomic Receptors

Autonomic receptors are broadly divided into those for ACh (cholinergic receptors) and those for catecholamines such as NE or EPI (adrenergic receptors or adrenoceptors). As we shall see later, subdivisions of each of these families of receptors are based on sensitivity to various agonist and antagonist drugs.

Cholinergic receptors were originally divided and named on the basis of sensitivity to alkaloids that mimicked some, but not all, of the actions of ACh. These alkaloids are present in the fly agaric mushroom, Amanita muscaria, and in the tobacco plant, Nicotiana tabacum. The alkaloids are muscarine and nicotine, respectively. Thus, cholinergic receptors are broadly classified as muscarinic (mAChR) or nicotinic (nAChR). The 3-dimensional structures of muscarine and nicotine molecules are fairly rigid and differ significantly. By contrast, ACh can assume 3-dimensional structures that are similar to muscarine on the one hand and nicotine on the other hand. Thus, one neurotransmitter molecule can interact with quite different receptor proteins, based on its molecular flexibility.

Nicotinic receptors are located postsynaptically in all autonomic ganglia and at the NMJ. At these junctions nicotinic receptors function as the excitatory receptor for the postsynaptic cell. Release of a sufficient quantity of ACh from the adjoining presynaptic cell causes an excitatory response in autonomic ganglion cells and in somatic muscle fibers.

Muscarinic receptors are located postsynaptically at the parasympathetic neuroeffector junction. At these junctions muscarinic receptors function either to increase or decrease the activity of the effector cells. Muscarinic receptors are also located postsynaptically at the neuroeffector junction of sympathetic fibers in sweat glands. At this junction muscarinic receptors function to increase sweating. Drugs that block muscarinic receptors can thus interfere with sweating. Another important site of muscarinic receptors is on endothelial cells of blood vessels. Although these muscarinic receptors are not innervated by cholinergic nerve fibers, they are sensitive to circulating molecules.

In 1948, adrenergic receptors were subdivided into alpha and beta by Ahlquist (a graduate of the University of Washington). The distinction was based on sensitivities of different organs to catecholamines of closely related structure. Regulation of the functions of different organs depends to a greater or lesser extent on alpha or beta receptors. Pharmacological differentiation of alpha and beta receptors, and application of this technology to the treatment of disease, is an outstanding biomedical achievement.

Alpha receptors are located postsynaptically at sympathetic neuroeffector junctions of many organs. In general, alpha receptors mediate excitation or increased activity of the effector cells. Vascular smooth muscle is an important site of alpha receptors. SNS activity maintains vascular tone, and thus blood pressure, by maintaining a tone of neurotransmitter on vascular alpha receptors.

Beta receptors are also located postsynaptically at sympathetic neuroeffector junctions of many organs. In general, beta receptors mediate relaxation or decreased activity of the effector cells. Thus, blood vessels dilate and uterine smooth muscle relaxes in response to activation of beta receptors. Heart muscle is an important exception to this rule. Activation of beta adrenoceptors in heart increases the automaticity and contractility of all parts of the heart.

Cholinergic receptors

Cholinergic, receptors mediate the actions of acetylcholine (ACh). Other choline esters such as methacholine (Mecholyl®) or carbamylcholine (Carbachol®) mimic the actions of ACh at the same receptors. Cholinergic receptors are subdivided into:

muscarinic

nicotinic

Ganglionic and other neural muscarinic receptors (M1) are apparently involved in CNS transmission. They may modulate classical ganglionic transmission process. They have been implicated in promoting the late EPSP of ganglion cells.. These receptors are classified as muscarinic because they are blocked by atropine. Oxotremorine and McN-A-343 activate these receptors somewhat selectively. Pirenzepine is a relatively selective antagonist of M1 receptors.

Classical muscarinic receptors (M2) (and M3, not shown) subserve effects such
as salivation, urination, defecation, pupillary constriction, vasodilation,
cardiac slowing, depressed AV nodal conduction, and bronchoconstriction.
The classical site of muscarinic receptors is at the postganglionic parasympathetic
neuroeffector junction in smooth muscle, heart, and exocrine glands. However,
muscarinic receptors also exist on effectors cells, even in the absence of
cholinergic innervation. Prototype agonists include muscarine and ACh. The
prototype non-selective antagonist is atropine. AF-DX
116 is a selective antagonist of M2 receptors and hexahydrosilafenidol is
a selective antagonist of M3 receptors.

The main contribution of such selective
experimental agents is that they provided evidence for the existence of
more than one type of muscarinic receptor, as well as raising the possibility
of pharmacologically selective agonism or antagonism. Tiotropium, a selective
antagonist of M3 receptors has recently been approved for treatment of chronic
obstructive pulonary disease (COPD). One of the advantages tiotropium
(over atropine, for example) is that it generally blocks only postsynaptic
M3 receptors (that promote bronchoconstriction) but does not block presynaptic
M2 receptors (that inhibit the release of ACh). Blockade of presynaptic M2
receptors tends to increase the release of acetylcholine and worsen COPD
symptoms). Thus, tiotropium is a prime example of the therapeutic significance
of being able to pharmacologically distinguish between receptor subtypes.

Modern molecular biology techniques have identified at least 5 different muscarinic
receptors. At present, the pharmacologic and/or therapeutic significance
of M4 and M5 is not yet definitive

Nicotinic receptors are cholinergic receptors which, when activated, mediate most of the actions of nicotine and some of those ACh. Examples of nicotinically-mediated effects include the release of catecholamines from the adrenal medulla, ganglionic transmission, and transmission of the somatic neuromuscular junction (NMJ). Autonomic and somatic nicotinic receptors are distinct pharmacologically.

Somatic muscle nicotinic receptors, (NM) are receptors for which prototype agonists include nicotine, and ACh. Phenyltrimethylammonium (PTMA) is a selective agonist. The classical antagonist of the NM receptor is the non-depolarizing neuromuscular junction blocker, d-tubocurarine (Tubarine®). An ingredient of snake venom, alpha-bungarotoxin, binds almost irreversibly to and blocks the NM receptor.

Drugs which act initially as depolarizing neuromuscular junction blockers (NM agonists), and then produce neuromuscular junction blockade even when the motor end plate has repolarized, include decamethonium and succinylcholine (Anectine®). It may be that these agents produce initial block by depolarizing the motor-end plate and then, because they are not rapidly broken down by acetylcholinesterase, promote receptor desensitization.

This diagram summarizes the cholinergic receptor system and some of its agonists and antagonists. The arrows are meant to show the range of selectivity of the various drugs for most practical purposes. Apparent selectivity of agonists or antagonists may be lost at relatively high concentrations. Relative affinities of a given drug for different receptors may be implied, but the affinities of different drugs are not shown in this qualitative guide. For such information, you will need to consult data on the apparent Kd, IC50 or other comparable measurements.

Adrenergic receptors

Adrenergic receptors, also called adrenoceptors, mediate the actions of epinephrine (Adrenalin®) and related compounds. Adrenergic receptors can be acted upon by a variety of agonists and antagonists, most of which are related to beta-phenylethylamine. The classical site of adrenergic receptors is the sympathetic neuroeffector junction. As in the case of cholinergic receptors, however, adrenergic receptors may exist on the cells of effector organs, even in the absence of sympathetic innervation. In other words, not necessarily all adrenergic receptors are innervated. Adrenergic drugs mimic the actions of epinephrine and are also called sympathomimetics. Direct-acting sympathomimetics act by direct stimulation of adrenergic receptors.

Adrenergic receptors may be divided into two major types according to drug (especially antagonist) potency on the receptors. Alpha receptors, when activated, generally produce excitatory responses of smooth muscle in which they are located. Beta receptors, when activated, generally produce inhibitory responses of smooth muscle in which they are located.

Alpha2 receptors are sensitive to blockade by yohimbine. Alpha2 receptors are found mainly presynaptically on sympathetic postganglionic nerve terminals. Activation of the presynaptic alpha2 receptors inhibits the release of NE and the term autoreceptor came into fashion. Some of the pharmacological effects of alphamethyl-norephinephrine (functioning as a false transmitter produced from alphamethyl DOPA) may be due to activation of alpha2 receptors and selective presynaptic inhibition of the release of NE.

Recently it has been shown that some alpha2 receptors are present postsynaptically so the distinction between alpha1 and alpha2 receptors should be considered functional, rather than anatomic. Molecular biology has subdivided the alpha1receptors into alpha1A, alpha1B, and alpha1D. The alpha2 receptors subdivide into alpha2A (probably is the presynaptic autoreceptor), alpha2B and alpha2C. The major antihypertensive action of selective alpha agonists such as clonidine (Catapres®), probably occurs as a result of agonism of alpha2A receptors in the CNS.

Beta receptors when activated, generally produce "inhibitory" responses of smooth muscle in which they are located. Bronchodilation and vasodilation in some vascular beds can be produced by activation of beta-receptors. The classical agonist of beta-receptors is isoproterenol (Isuprel®). The classical antagonist is propranolol (Inderal®). Some beta-receptors subserve "excitatory" responses. For example, in heart, beta-receptors are excitatory. Sympathetic positive chrono- and inotropism are mediated through excitation of beta-receptors. Therapeutic differentiation of beta-receptors is well established. Thus, we may consider:

Beta1 receptors, when activated, produce cardiac positive chrono- and inotropic responses and lipolysis. The beta receptors of the heart are somewhat unique. For example, they produce cardiac excitation and, although NE does not act on beta-receptors in vascular smooth muscle, it is equipotent with epinephrine in stimulating the heart. Isoproterenol acts as an agonist of beta1 receptors. Selective antagonists of beta1 receptors include metoprolol (Lopressor®) and CGP 20712A.

Beta2 receptors, when activated, produce bronchodilation, vasodilation, and uterine relaxation. Selective beta2 agonists, which are useful in the treatment of asthma, include terbutaline (Brethine®). Propranolol, which blocks both beta1 and beta2 receptors is generally contraindicated in bronchial asthma. ICI 118551 is a selective antagonist of beta2 receptors. labetalol (Normodyne®) is a clinically useful drug which is a selective alpha1 antagonist, and a non-selective antagonist of both beta1 and beta2 receptors.

Beta3 receptors, when activated, produce lipolysis in adipose tissue.
The significance and therapeutic application of this knowledge is still in
its infancy. BRL
37344 is a relatively selective agonist of beta3 receptors. Antagonists
include ICI
118551 and CGP
20712A, each of which is selective for beta1 and beta2 receptors, respectively.

This diagram summarizes the adrenergic receptor system and some of its agonists and antagonists. The arrows are meant to show the range of selectivity of the various drugs for most practical purposes. Apparent selectivity of agonists or antagonists may be lost at relatively high concentrations. Relative affinities of a given drug for different receptors may be implied, but the affinities of different drugs are not shown in this qualitative guide. For such information, you will need to consult data on the apparent Kd, IC50 or other comparable measurements.